Synthesis of 1,2-Aminoalcohols through Enantioselective Aminoallylation of Ketones by Cu-Catalyzed Reductive Coupling

Herein, we report the development of a catalytic enantioselective addition of N-substituted allyl equivalents to ketone electrophiles through use of Cu-catalyzed reductive coupling to access important chiral 1,2-aminoalcohol synthons in high levels of regio-, diastereo-, and enantioselectivity. Factors affecting enantioinduction are discussed including the identification of a reversible ketone allylation step that has not been previously reported in Cu-catalyzed reductive coupling.

General. 1 H NMR spectra were recorded on Bruker 600 MHz spectrometers. Chemical shifts are reported in ppm from tetramethylsilane with the solvent resonance as an internal standard (CDCl3: 7.26 ppm). Data are reported as follows: chemical shift, integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, h = hextet, hept = heptet, br = broad, m = multiplet), and coupling constants (Hz). 13 C NMR was recorded on a Bruker 600 MHz (151 MHz) instrument with complete proton decoupling. Chemical shifts are reported in ppm from tetramethylsilane with the solvent as the internal standard (CDCl3: 77.0 ppm). Chiral HPLC analyses were performed on a Shimadzu Prominence i-series LC-2030C using chiral Daicel columns purchased from Chiral Technologies, Inc. Liquid chromatography was performed using forced flow (flash chromatography) on silica gel purchased from Silicycle. Thin layer chromatography (TLC) was performed on glass-backed 250 μm silica gel F254 plates purchased from Silicycle. Visualization was achieved using UV light, a 10% solution of phosphomolybdic acid in EtOH, or potassium permanganate in water followed by heating. HRMS was collected using a Jeol AccuTOF-DART TM mass spectrometer using DART source ionization. All reactions were conducted in oven or flame dried glassware under an inert atmosphere of nitrogen or argon with magnetic stirring unless otherwise noted. Solvents were obtained from VWR as HPLC grade and transferred to septa sealed bottles, degased by Ar sparge, and analyzed by Karl-Fischer titration to ensure water content was < 600 ppm. Me(MeO)2SiH was purchased from Alfa Aesar and used as received. Allenamides 11 and 23 were prepared in one step as described in the literature. 1 Ketones were purchased from Sigma Aldrich, TCI America, Alfa Aesar, S2 or Oakwood Chemicals and used as received. Ligands were obtained from the Strem Chemical Company. All other materials were purchased from VWR, Sigma Aldrich, Combi-Blocks, Alfa-Aesar, or Strem Chemical Company and used as received.  2 SiH in 0.5 mL of toluene at rt for 24 h. b Yield of 12a determined by quantitative 1 H NMR spectroscopy on the unpurified reaction mixture using dimethyl fumarate as the analytical standard. c The ratio was determined by 1 H NMR spectroscopic analysis on the unpurified reaction mixture. d Enantiomeric ratios were determined by chiral HPLC analysis. e b:l refers to the ratio of branched to linear isomers as defined by: (12a + 13a) : l-12a.   2 SiH in 0.5 mL of solvent at rt for 24 h. b Yield of 12a determined by quantitative 1 H NMR spectroscopy on the unpurified reaction mixture using dimethyl fumarate as the analytical standard. c The ratio was determined by 1 H NMR spectroscopic analysis on the unpurified reaction mixture. d Enantiomeric ratios were determined by chiral HPLC analysis. e b:l refers to the ratio of branched to linear isomers as defined by: (12a + 13a) : l-12a.
General procedure for the branched-selective Cu(W8) catalyzed reductive coupling by Method A.
To a 20 mL crimp-cap vial with stir-bar in an Ar-filled glove-box was charged 2.3 mg (0.0125 mmol) of Cu(OAc)2 and 14.0 mg (0.0150 mmol) of Walphos-8. Toluene (0.5 mL) was then added, and the mixture was allowed to stir for 10 min. Allenamide 11 (47.0 mg, 0.375 mmol) followed by the ketone (0.250 mmol) was then charged, and the vial was sealed with a crimp-cap septum and removed from the glove-box. The reaction was then cooled in an ice bath, and dimethoxymethylsilane (62 μL, 0.5 mmol) was then charged by syringe (caution: dimethoxymethylsilane should be handled in a well-ventilated fume hood because it is known to cause blindness. Syringes were quenched with 2M NaOH, gas evolution!, prior to disposal) The mixture was then allowed to warm to rt and stirred for 24 h. The reaction was then quenched by the addition of 95 mg of NH4F and 1.5 mL of MeOH followed by agitation at rt for 30 min -1 h. To the mixture was then charged 5 mL of 5% NaHCO3 followed by extraction with CH2Cl2 (2x4mL). The combined organics were dried with Na2SO4 and concentrated in vacuo. An aliquot of the crude mixture was analyzed by 1 HNMR spectroscopy to determine the dr and b/l ratio. The crude residue was then purified by flash chromatography on silica gel to afford the desired product. Enantioselectivity was determined by chiral HPLC analysis relative to authentic racemate prepared by the same method using PCy3 as ligand.

General procedure for the branched-selective Cu(W8) catalyzed reductive coupling by Method B.
To a 20 mL crimp-cap vial with stir-bar in an Ar-filled glove-box was charged 2.3 mg (0.0125 mmol) of Cu(OAc)2 and 14.0 mg (0.0150 mmol) of Walphos-8. α,α,α-Trifluorotoluene (0.5 mL) was then added, and the mixture was allowed to stir for 10 min. Allenamide 11 (47.0 mg, 0.375 mmol) followed by the ketone (0.250 mmol) and t BuOH (48 µL, 0.500 mmol) was then charged. The vial was then sealed with a crimp-cap septum and removed from the glove-box. The reaction was then cooled in an ice bath, and dimethoxymethylsilane (62 μL, 0.5 mmol) was then charged by syringe (caution: dimethoxymethylsilane should be handled in a well-ventilated fume hood because it is known to cause blindness. Syringes were quenched with 2M NaOH, gas evolution!, prior to disposal) The mixture was then allowed to warm to rt and stirred for 24 h. The reaction was then quenched by the addition of 95 mg of NH4F and 1.5 mL of MeOH followed by agitation at rt for 30 min -1 h. To the mixture was then charged 5 mL of 5% NaHCO3 followed by extraction with CH2Cl2 (2x4mL). The combined organics were dried with Na2SO4 and concentrated in vacuo. An aliquot of the crude mixture was analyzed by 1 HNMR spectroscopy to determine the dr and b/l ratio. The crude residue was then purified by flash chromatography on silica gel to afford the desired product. Enantioselectivity was determined by chiral HPLC analysis relative to authentic racemate prepared by the same method using PCy3 as ligand.

(S)-3-(4-hydroxy-4-methylpent-1-en-3-yl)oxaxolidin-2-one (12t):
According to the general procedure, the product was purified by silica gel chromatography (eluent: 0 -40% EtOAc in CH2Cl2) to provide 23.6 mg (51%) of 12t as a white solid as a single diasteromer. The stereochemistry was assigned by analogy to that of 12a. Rf = 0.24 (40% EtOAc/CH2Cl2). 1  To a 20 mL crimp-cap vial with stir-bar in an Ar-filled glove-box was charged 9.2 mg (0.05 mmol) of Cu(OAc)2 and 56.0 mg (0.06 mmol) of Walphos-8. α,α,α-Trifluorotoluene (2.0 mL) was then added, and the mixture was allowed to stir for 10 min. Allenamide 11 (188.0 mg, 1.5 mmol) followed by ketone 8b (1.0 mmol) and t BuOH ( 0.192 mL, 2.00 mmol) was then charged. The vial was then sealed with a crimp-cap septum and removed from the glove-box. The reaction was then cooled in an ice bath, and dimethoxymethylsilane (0.248 μL, 2.0 mmol) was then charged by syringe (caution: dimethoxymethylsilane should be handled in a well-ventilated fume hood because it is known to cause blindness. Syringes were quenched with 2M NaOH, gas evolution!, prior to disposal) The mixture was then allowed to warm to rt and stirred for 24 h. The reaction was then quenched by the addition of 380 mg of NH4F and 6.0 mL of MeOH followed by agitation at rt for 30 min -1 h. The crude mixture was then transferred to a separatory funnel to which 20 mL of 5% NaHCO3 was then charged and agitated. The mixture was then extracted with CH2Cl2 (2x10mL). The combined organics were dried with Na2SO4 and concentrated in vacuo. An aliquot of the crude mixture was analyzed by 1 HNMR spectroscopy to determine the dr (>99) and b/l (>99) ratio. The crude residue was then purified by flash chromatography on silica gel (gradient, 0 -20% EtOAc in CH2Cl2). The first spot to elute was isolated as a (W8)Cu complex that was then decomplexed for recovery of W8 (see below). The product spot (Rf = 0.31, 10% EtOAc in CH2Cl2) was then collected and concentrated in vacuo to afford 188 mg (72%) of 12b. Enantioselectivity was determined by chiral HPLC analysis to be 96:4.

Recovery of W8:
The (W8)Cu complex obtained from the above reaction was further purified by flash chromatography on silica gel (gradient, 0 -15% EtOAc in hexanes) to afford 71.0 mg of an orange solid. This material was then dissolved in 3.0 mL of 2:1 pentane:MTBE and then 1 mL of 50% NH4OH solution was added. The mixture was then agitated vigorously for 5 minutes upon which the lower blue aqueous layer was removed. The organic layer was then washed twice with 1 mL of 50% NH4OH, dried with Na2SO4 and concentrated in vacuo to yield 45.1 mg (81% recovery) of W8 as an orange solid. Use of this recovered ligand in the Cu-catalyzed reductive coupling with propiophenone provided identical results to that obtained with the commercially obtained W8.

Large Scale recrystallization of 12a:
To a 20 mL crimp-cap vial with a stir-bar was charged 357.0 mg of 12a of 91 wt% with 90/10 er. To the vial was then added 2.0 mL of 30% EtOAc/Hexanes solution and heated to 40 o C while stirring vigorously. After 30 min of stirring, the mixture was allowed to cool to rt and stir for and additional 30 min and then filtered to yield 237 mg (73%) of analytically pure 12a with >99:1 er.

Oxazolidinone Removal:
To a solution of 210 mg (0.850 mmol) of 12a in 2.0 mL of THF at 0 o C was charged 34 mg (0.850 mmol) of NaH. The reaction was then allowed to warm to room temperature and stirred for 1 h. The reaction was then quenched by the addition of 5 mL of 1M HCl and extracted with CH2Cl2 (3 X 10 mL). The combined organics were dried with Na2SO4 and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, gradient, 20 -50% EtOAc/hexanes) to afford 209.1 mg (99%) of 13a as a thick waxy oil. Rf = 0.18 (10% EtOAc/CH2Cl2). 1  To a solution of 209.1 mg (0.846 mmol) of 13a in 4.2 mL of CH2Cl2 at 0 o C was charged 141 μL (1.02 mmol) of triethylamine followed by 177 mg (0.931 mmol) of TsCl. The mixture was stirred for 30 min at 0 o C, allowed to warm to rt and stirred for 8 h. To the mixture was charged 2 mL of 10% NH4Cl followed by extraction with CH2Cl2 (3x2mL). The combined organics were dried with anhydrous Na2SO4, and volatile material was removed in vacuo. The crude residue was then dissolved in 8.0 mL of glyme and charged with 360 mg (2.54 mmol) of NaI and 383 μL (2.54 mmol) of DBU and refluxed for 8 h. The mixture was diluted with 30 mL of 1:1 mixture of Et2O and H2O and stirred for 10 min upon which organics were extracted with Et2O (2x10 mL). The combined organic layers were washed with brine, dried with anhydrous Na2SO4, filtered, and volatiles removed in vacuo. The crude residue was then dissolved in 5.0 mL of THF in a 20 mL scintillation vial. To the solution was added 1.7 mL (8.46 mmol) of 5.0 M aqueous H2SO4. The vial was purged with argon, sealed, and immersed in an oil bath at 50 o C. After 2.5 h, the reaction was cooled to rt and 10 mL of saturated aqueous NaHCO3 was charged. The mixture was extracted with CH2Cl2 (3x5mL), dried with anhydrous Na2SO4, and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, gradient, hexanes to 60% EtOAc/hexanes) to afford 134.2 mg (78%) of 20 as a White solid. Rf = 0.19 (40% EtOAc/hexanes). Spectral data was identical to that made previously. Hydrometalation of 11 by a W8CuH catalyst affords SI-2 8 that adds to ketone 8 through a closed chairlike transition state 2,6,9,10 providing branched intermediate SI-3. The addition step (SI-2 + 8 → SI-3) is likely stereodetermining, however, the enantiopurity of product 12 derived from this intermediate will be affected if this addition step were reversible. For instance, the subsequent silylation or migration steps of SI-3 for catalytic turnover affording products 12 or 13, respectively may enhance or erode the initial stereoselectivity set in the addition step since turnover of the initially formed diastereomeric mixture of SI-3 will proceed at different rates through diastereomeric transition states. Under this scenario, the addition step could be highly stereoselective providing SI-3 in high d.r., but if the minor diastereomer undergoes migration to SI-5 faster than the major one, overall poor enantioselectivity of 13 would be obtained, as was observed. This effect is exacerbated when using more sterically demanding ketones (e.g. propiophenone: R 1 = Et) whereby the migration rate would increase due to the enhanced Thorpe-Ingold effect while the silylation rate may decrease due to the increased steric demand. This can account for the increased amounts of 13 obtained when utilizing propiophenone.

Attempted retroallylation of 12a:
A crimp-cap vial with magnetic stir-bar was charged with 1.7 mg (0.0091 mmol) of CuI, 1.0 mg (0.0091 mmol) of KO t Bu, 2.6 mg (0.0091 mmol) of PCy3, and 0.20 mL of THF in the glove-box, and the resultant mixture was allowed to stir for 30 min. Next, 12a (15.0 mg, 0.0607 mmol) was charged and the vial was sealed, removed from the glove-box, and allowed to stir at rt for 24 h. To the mixture was then added 0.2 mL of 50% aqueous NH4OH and 1.0 mL of water followed by extraction with CH2Cl2 (2x1mL). The combined organics were dried with anhydrous Na2SO4 and concentrated in vacuo. The crude mixture was then analyzed by quantitative 1 H NMR spectroscopy using dimethyl fumarate as analytical standard.

Synthesis of b-17:
The Cu-catalyzed reductive coupling of N-allenyl pyrrolidinone and acetophenone (8a) was performed according to the Method A general procedure. The products were purified by silica gel chromatography (eluent: 0 -30% EtOAc in CH2Cl2) to provide 35.5 mg (58%) of b-17 as a white solid as a single diastereomer and 22.0 mg (36%) of l-17 as a thick oil. The enantiopurity of b-17 was determined by chiral HPLC analysis relative to authentic racemic material prepared using PCy3 as ligand in the reductive coupling reaction. The stereochemistry of b-17 was assigned by analogy to that of 12a A crimp-cap vial with magnetic stir-bar was charged with 2.3 mg (0.012 mmol) of CuI, 1.4 mg (0.012 mmol) of KO t Bu, 0.012 mmol of ligand (W8 or PCy3), and 0.50 mL of THF in the glove-box, and the resultant mixture was allowed to stir for 30 min. Next, b-17 (30.0 mg, 0.122 mmol) was charged and the vial was sealed, removed from the glove-box, and allowed to stir at rt for 24 h. To the mixture was then added 0.5 mL of 50% aqueous NH4OH and 1.0 mL of water followed by extraction with EtOAc (3x2mL). The combined organics were dried with anhydrous Na2SO4 and concentrated in vacuo. The crude mixture was then analyzed by quantitative 1 H NMR spectroscopy using dimethyl fumarate as analytical standard to determine the amounts of b-17, l-17, 8a, 18, and 19. The identity of N-allyl pyrrolidine-2-one (18) 4 and (Z)-N-propenyl pyrrolidine-2-one (19) 5 were confirmed in relation to authentic material. The enantiopurity of recovered b-17 (silica gel chromatography) was determined by chiral HPLC analysis. A proposed mechanism is outlined in Figure SI-2. Alcohol exchange leads to SI-8 that upon retroallylation to release acetophenone (8a) affords N-allyl Cu-complex l-SI-9 that can equilibrate to b-SI-9. Reaction of b-SI-9 with acetophenone leads to formation of linear isomer l-17 whereas reaction of l-SI-9 with acetophenone regenerates b-17 rationalizing the change in er for recovered b-17 observed in this experiment. Protonolysis of l-SI-9 and b-SI-9 is proposed to occur through chair-like transition states SI-TS1 and SI-TS2, respectively. The exclusive formation of the Z-stereoisomer of 19 in these experiments strongly suggests this type of protonolysis pathway that is similar to that for the addition of related analogues of b-SI-9 to ketone electrophiles providing Z-enamides. 6,7 However, direct protonolysis of l-SI-9 and b-SI-9 cannot be ruled out.

Analysis of product 12a enantiopurity throughout the progress of the reaction:
Three reactions were setup at the same time according to the Method A general procedure utilizing 9.7 L (10 mg, 0.083 mmol) of acetophenone. Each reaction was quenched and worked up at different time points and 12a was isolated and the enantiopurity determined (Table SI-4). The enantiopurity did not vary over time.